The present invention relates to compounds that are useful for treating inflammatory and immune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
Inflammation results from a cascade of events that includes vasodilation accompanied by increased vascular permeability and exudation of fluid and plasma proteins. This disruption of vascular integrity precedes or coincides with an infiltration of inflammatory cells. Inflammatory mediators generated at the site of the initial lesion serve to recruit inflammatory cells to the site of injury. These mediators (chemokines such as IL-8, MCP-1, MIP-1, and RANTES, complement fragments and lipid mediators) have chemotactic activity for leukocytes and attract the inflammatory cells to the inflamed lesion. These chemotactic mediators which cause circulating leukocytes to localize at the site of inflammation require the cells to cross the vascular endothelium at a precise location. This leukocyte recruitment is accomplished by a process called cell adhesion.
Cell adhesion occurs through a coordinately regulated series of steps that allow the leukocytes to first adhere to a specific region of the vascular endothelium and then cross the endothelial barrier to migrate to the inflamed tissue (Springer, T. A., 1994, xe2x80x9cTraffic Signals for Lymphocyte Recirculation and Leukocyte Emigration: The Multistep Paradigmxe2x80x9d, Cell, 76: 301-314; Lawrence, M. B., and Springer, T. A., 1991, xe2x80x9cLeukocytes"" Roll on a Selectin at Physiologic Flow Rates: Distinction from and Prerequisite for Adhesion Through Integrinsxe2x80x9d, Cell, 65: 859-873; von Adrian, U., Chambers, J. D., McEnvoy, L. M., Bargatze, R. F., Arfos, K. E, and Butcher, E. C., 1991, xe2x80x9cTwo-Step Model of Leukocyte-Endothelial Cell Interactions in Inflammationxe2x80x9d, Proc. Nat""l. Acad. Sci. USA, 88: 7538-7542; and Ley, K., Gaehtgens, P., Fennie, C., Singer, M. S., Lasky, L. H. and Rosen, S. D.,1991, xe2x80x9cLectin-Like Cell Adhesion Molecule 1 Mediates Rolling in Mesenteric Venules in vivoxe2x80x9d, Blood 77: 2553-2555). These steps are mediated by families of adhesion molecules such as integrins, Ig supergene family members, and selectins which are expressed on the surface of the circulating leukocytes and on the vascular endothelial cells. The first step consists of leukocytes rolling along the vascular endothelial cell lining in the region of inflammation. The rolling step is mediated by an interaction between a leukocyte surface oligosaccharide, such as Sialylated Lewis-X antigen (SLex), and a selectin molecule expressed on the surface of the endothelial cell in the region of inflammation. The selectin molecule is not normally expressed on the surface of endothelial cells but rather is induced by the action of inflammatory mediators such as TNF-xcex1 and interleukin-1. Rolling decreases the velocity of the circulating leukocyte in the region of inflammation and allows the cells to more firmly adhere to the endothelial cell. The firm adhesion is accomplished by the interaction of integrin molecules that are present on the surface of the rolling leukocytes and their counter-receptors (the Ig superfamily molecules) on the surface of the endothelial cell. The Ig superfamily molecules or CAMs (Cell Adhesion Molecules) are either not expressed or are expressed at low levels on normal vascular endothelial cells. The CAM""s, like the selecting, are induced by the action of inflammatory mediators like TNF-alpha and IL-1. The final event in the adhesion process is the extravasation of leukocytes through the endothelial cell barrier and their migration along a chemotactic gradient to the site of inflammation. This transmigration is mediated by the conversion of the leukocyte integrin from a low avidity state to a high avidity state. The adhesion process relies on the induced expression of selectins and CAM""s on the surface of vascular endothelial cells to mediate the rolling and firm adhesion of leukocytes to the vascular endothelium.
The interaction of the intercellular adhesion molecule ICAM-1 (cd54) on endothelial cells with the integrin LFA-1 on leukocytes plays an important role in endothelial-leukocyte contact. Leukocytes bearing high-affinity LFA-1 adhere to endothelial cells through interaction with ICAM-1, initiating the process of extravasation from the vasculature into the surrounding tissues. Thus, an agent which blocks the ICAM-1/LFA-1 interaction suppresses these early steps in the inflammatory response. Consistent with this background, ICAM-1 knockout mice have numerous abnormalities in their inflammatory responses.
The present invention discloses compounds which bind to the interaction-domain (I-domain) of LFA-1, thus interrupting endothelial cell-leukocyte adhesion by blocking the interaction of LFA-1 with ICAM-1, ICAM-3, and other adhesion molecules. These compounds are useful for the treatment or prophylaxis of diseases in which leukocyte trafficking plays a role, notably acute and chronic inflammatory diseases, autoimmune diseases, tumor metastasis, allograft rejection, and reperfusion injury.
The present invention is directed to compounds of Formula I 
or pharmaceutically acceptable salts, optical isomers, or prodrugs thereof,
wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, cycloalkyl and carboxaldehyde, or a group of Formula II defined as 
xe2x80x83subject to the proviso that one or more than one of R1 or R3 is a group of Formula II as defined above;
wherein D, B, Y and Z at each occurrence are independently selected from the group consisting of xe2x80x94CR6xe2x95x90, xe2x80x94CR7R8xe2x80x94, C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Nxe2x95x90, and xe2x80x94NR9xe2x80x94;
n is an integer of zero to three;
R6, R7, R8, and R9, at each occurrences are each independently selected from the group consisting of hydrogen, alkyl, carboxy, hydroxyalkyl, alkylaminocarbonylalkyl dialkylaminocarbonylalkyl and carboxyalkyl; and
R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; or
R10 and R11 are taken together with N to form a three to seven membered unsubstituted heterocyclyl ring, or a three to seven membered substituted heterocyclyl ring substituted with one or more than one substituent R13, wherein R13, at each occurrence is independently selected from the group consisting of alkyl, alkylene, alkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylalkylaminocarbonyl, hydroxy, hydroxyalkyl, hydroxyalkoxyalkyl, carboxy, carboxyalkyl, carboxycarbonyl, carboxaldehyde, alkoxycarbonyl, arylalkoxycarbonyl, aminoalkyl, aminoalkanoyl, aminocarbonyl, carboxamido, alkoxycarbonylalkyl, carboxamidoalkyl, cyano tetrazolyl, alkanoyl, hydroxyalkanoyl, alkanoyloxy, alkanoylamino, alkanoyloxyalkyl, alkanoylaminoalkyl, sulfonate, alkylsulfonyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl and hererocyclylsulfonylaminocarbonyl;
wherein A is an unsubstituted aryl group, an unsubstituted heterocyclyl group, a substituted aryl group, or a substituted heterocyclyl group, substituted with one or more than one substituent R12, wherein R12, at each occurrence, is independently selected from the group consisting of halogen, alkyl, aryl, haloalkyl, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkoxy, hydroxyalkyl, aminoalkyl, aminocarbonyl, alkyl(alkoxycarbonylalkyl) aminoalkyl, heterocyclyl, heterocyclylalkyl, carboxaldehyde, carboxaldehyde hydrazone, carboxamide, alkoxycarbonylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxythioalkoxy, carboxycycloalkoxy, thioalkoxy, carboxyalkylamino, trans-cinnamyl, hydroxyalkylaminocarbonyl, cyano, heterocyclylalkylamino, and heterocyclylalkylaminocarbonyl; and
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are unsubstituted or substituted with at least one electron donating or electron withdrawing group.
Presently preferred compounds of Formula I have R3 as Formula II (shown above), with substituents defined as above, R1 and R2 each independently as hydrogen, halogen, haloalkyl or nitro; and R4 and R5 each independently as hydrogen or alkyl.
The present invention is also directed to compounds of Formula III 
wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, cycloalkyl and carboxaldehyde;
D, B, Y and Z are as defined above for Formula I;
R12, at each occurrence, is independently selected from die group consisting of halogen, alkyl, haloalkyl, alkoxy, carboxyalkoxy, carboxyalkyl and heterocyclyl;
p is an integer of zero to five; and
wherein R1, R2, R4, R5, R10, R11 and R12 are unsubstituted or substituted with at least one electron donating group or electron withdrawing group.
Presently most preferred, but not required, compounds of Formula III have p as one; R4 and R5 as hydrogen; R12 as halogen, alkyl, carboxyalkoxy, carboxyalkyl or heterocyclyl; and R10 and R11 are taken together with N to form a three to seven membered unsubstituted heterocyclyl ring, or a three to seven membered substituted heterocyclyl ring; said ring being piperidine, piperazine, morpholine, pyrrolidine or azetidine.
Presently most preferred, but not required, compounds are of Formula IV 
wherein D and B axe each independently selected from the group consisting of xe2x80x94Nxe2x95x90 and xe2x80x94CR6xe2x95x90;
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen and haloalkyl;
R10 and R11 are as defined above for Formula I;
R12, at each occurrence, is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, carboxyalkoxy, carboxyalkyl and heterocyclyl;
p is an integer of zero to five; and
wherein R1, R2, R10, R11, and R12 are unsubstituted or substituted with at least one electron donating group or electron withdrawing group.
Presently most preferred, but not required, compounds are of Formula IV, where p can be one; R12 can be halogen, alkyl, alkoxy, carboxyalkoxy, carboxyalkyl or heterocyclyl; and R10 and R11 can be taken together with N to form a three to seven membered heterocyclyl ring; said ring being piperidine, piperazine, morpholine, pyrrolidine or azetidine.
The compounds represented by structural Formula I, above, may be prepared by synthetic processes or by metabolic processes. Processes for the preparation of the compounds of the present invention by metabolic processes include those occurring in the human or animal body (in vivo) or by processes occurring in vitro.
The present invention is also directed to a method of treatment or prophylaxis in which the inhibition of inflammation or suppression of immune response is desired, comprising administering an effective amount of a compound having Formula I.
In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
The term xe2x80x9calkanoylxe2x80x9d as used herein refers to an alkyl group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9calkanoylaminoxe2x80x9d as used herein refers to an alkanoyl group attached to the parent molecular group though an amino group.
The term xe2x80x9calkanoylaminoalkylxe2x80x9d as used herein refers to an alkanoylamino group attached to the parent molecular group through an alkyl group.
The term xe2x80x9calkanoyloxyxe2x80x9d as used herein refers to an alkanoyl group attached to the parent molecular group through an oxygen radical.
The term xe2x80x9calkanoyloxyalkylxe2x80x9d as used herein refers to an alkanoyloxy group attached to the parent molecular group through an alkyl group.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to an alkoxy group attached to the parent molecular group through an alkoxy group.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkoxy group attached to the parent molecular group through an alkyl group.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein refers to an alkoxy group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d as used herein refers to an alkoxycarbonyl group attached to the parent molecular group through an alkyl group.
The term xe2x80x9calkylxe2x80x9d as used herein refers to a saturated straight or branched chain group of 1-10 carbon atoms derived from an alkane by the removal of one hydrogen atom.
The term xe2x80x9calkyl(alkoxycarbonylalkyl)aminoxe2x80x9d as used herein refers to an amino group substituted with one alkyl group and one alkoxycarbonylalkyl group.
The term xe2x80x9calkyl(alkoxycarbonylalkyl)aminoalkylxe2x80x9d as used herein refers to an alkyl(alkoxycarbonylalkyl)amino group attached to the parent molecular group through an alkyl group.
The term xe2x80x9calkylenexe2x80x9d as used herein refers to a divalent group of 1-10 carbon atoms derived from a straight or branched chain alkane by the removal of two hydrogen atoms.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein refers to an alkyl radical attached to the parent molecular group through an xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9calkylsulfonylaminocarbonylxe2x80x9d as used herein refers to an alkylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
The term xe2x80x9caminoxe2x80x9d as used herein refers to a radical of the form xe2x80x94NRaRb, or to a radical of the form xe2x80x94NRaxe2x80x94, where Ra and Rb are independently selected from hydrogen, alkyl or cycloalkyl.
The term xe2x80x9caminoalkanoylxe2x80x9d as used herein refers to an amino group attached to the parent molecular group through an alkanoyl group.
The term xe2x80x9caminoalkylxe2x80x9d as used herein refers to an amino group attached to the parent molecular group through an alkyl group.
The term xe2x80x9caminocarbonylxe2x80x9d as used herein refers to an amino group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl groups of this invention can be optionally substituted with alkyl, halogen, hydroxy, or alkoxy substituents.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to an aryl group attached to the parent molecular group through an alkoxy group.
The term xe2x80x9carylalkoxycarbonylxe2x80x9d as used herein refers to an arylalkoxy group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9carylsulfonylxe2x80x9d as used herein refers to an aryl radical attached to the parent molecular group through an xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9carylsulfonylaminocarbonylxe2x80x9d as used herein refers to an arylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
The term xe2x80x9ccarboxaldehydexe2x80x9d as used herein refers to the radical xe2x80x94CHO.
The term xe2x80x9ccarboxaldehyde hydrazonexe2x80x9d as used herein refers to the radical xe2x80x94CHxe2x95x90Nxe2x80x94NRcRd, where Rc and Rd are independently selected from hydrogen, alkyl or cycloalkyl.
The terms xe2x80x9ccarboxamidexe2x80x9d or xe2x80x9ccarboxamidoxe2x80x9d as used herein refer to an amino group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9ccarboxamidoalkylxe2x80x9d as used herein refers to a carboxamido group attached to the parent molecular group through an alkyl group.
The term xe2x80x9ccarboxyxe2x80x9d as used herein refers to the radical xe2x80x94COOH.
The term xe2x80x9ccarboxyalkylxe2x80x9d as used herein refers to a carboxy group attached to the parent molecular group through an alkyl group.
The term xe2x80x9ccarboxyalkylaminoxe2x80x9d as used herein refers to a carboxyalkyl group attached to the parent molecular group through an amino group.
The term xe2x80x9ccarboxyalkoxyxe2x80x9d as used herein refers to a carboxy group attached to the parent molecular group through an alkoxy group.
The term xe2x80x9ccarboxycarbonylxe2x80x9d as used herein refers to a carboxy group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9ccarboxycycloalkoxyxe2x80x9d as used herein refers to a carboxy group attached to the parent molecular group through a cycloalkoxy group.
The term xe2x80x9ccarboxythioalkoxyxe2x80x9d as used herein refers to a carboxy group attached to the parent molecular group through a thioalkoxy group.
The term xe2x80x9ccyanoxe2x80x9d as used herein refers to the radical xe2x80x94CN.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-12 carbons derived from a cycloalkane by the removal of a single hydrogen atom. Cycloalkyl groups may be optionally substituted with alkyl, alkoxy, halo, or hydroxy substituents.
The term xe2x80x9ccycloalkoxyxe2x80x9d as used herein refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-12 carbons derived from a cycloalkane by the removal of a single hydrogen atom, linked to the parent molecular group through an oxygen atom. Cycloalkoxy groups may be optionally substituted with alkyl, alkoxy, halo or hydroxy groups.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to F, Cl, Br, or I.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to an alkyl group substituted with one or more halogen atoms.
The terms xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclylxe2x80x9d represent a 4-, 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds. The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d as used herein additionally refers to bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring. Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl, and the like.
Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as 
and the like.
Heterocyclics also include compounds of the formula 
where X* and Z* are independently selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94NHxe2x80x94 and xe2x80x94Oxe2x80x94, with the proviso that at least one of X* and Z* is not xe2x80x94CH2xe2x80x94, and Y* is selected from xe2x80x94C(O)xe2x80x94 and xe2x80x94(C(Rxe2x80x3)2)vxe2x80x94, where Rxe2x80x3 is hydrogen or alkyl of one to four carbons, and v is 1-3. These heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl, 1,3-benzimidazol-2-one and the like. The heterocycle groups of this invention can be optionally substituted with alkyl, halogen, hydroxy or alkoxy substituents.
The term xe2x80x9cheterocyclylalkylxe2x80x9d as used herein refers to a heterocyclic group attached to the parent molecular group through an alkyl group.
The term xe2x80x9cheterocyclylalkylaminoxe2x80x9d as used herein refers to an heterocyclylalkyl group attached to the parent molecular group through an amino group.
The term xe2x80x9cheterocyclylalkylaminocarbonylxe2x80x9d as used herein refers to a heterocyclylalkylamino group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9cheterocyclylaminoxe2x80x9d as used herein refers to a heterocyclyl group attached to the parent molecular group through an amino group.
The term xe2x80x9cheterocyclylcarbonylxe2x80x9d as used herein refers to a heterocyclyl group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9cheterocyclylsulfonylxe2x80x9d as used herein refers to a heterocyclyl radical attached to the parent molecular group through an xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cheterocyclylsulfonylaminocarbonylxe2x80x9d as used herein refers to a heterocyclylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
The term xe2x80x9chydroxyalkanoylxe2x80x9d as used herein refers to a hydroxy radical attached to the parent molecular group through an alkanoyl group.
The term xe2x80x9chydroxyalkoxyxe2x80x9d as used herein refers to a hydroxy radical attached to the parent molecular group through an alkoxy group.
The term xe2x80x9chydroxyalkoxyalkylxe2x80x9d as used herein refers to a hydroxyalkoxy group attached to the parent molecular group through an alkyl group.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to a hydroxy radical attached to the parent molecular group through an alkyl group.
The term xe2x80x9chydroxyalkylaminocarbonylxe2x80x9d as used herein refers to a hydroxyalkyl group attached to the parent molecular group through an aminocarbonyl group.
The term xe2x80x9cperfluoroalkylxe2x80x9d as used herein refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
The term xe2x80x9cphenylxe2x80x9d as used herein refers to a monocyclic carbocyclic ring system having one aromatic ring. The phenyl group can also be fused to a cyclohexane or cyclopentane ring. The phenyl groups of this invention can be optionally substituted with alkyl, halogen, hydroxy or alkoxy substituents.
The term xe2x80x9cpharmaceutically-acceptable prodrugsxe2x80x9d as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. The term xe2x80x9csulfonatexe2x80x9d as used herein refers to the radical xe2x80x94SO3H.
The term xe2x80x9ctetrazolexe2x80x9d or xe2x80x9ctetrazolylxe2x80x9d as used herein refers to the heterocyclic radical xe2x80x94CN4H.
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to an alkyl group attached to the parent molecular group through a sulfur atom.
The term xe2x80x9ctrans-cinnamylxe2x80x9d as used herein refers to an acrylamido group (aminocarbonylethenyl) attached to the parent molecular group through C-3 of the acrylamido group, such that the aminocarbonyl and the parent molecular group exist in a trans relationship about the ethenyl group.
The term xe2x80x9clowerxe2x80x9d refers to a C1-C6 unit for a particular functionality. For example, xe2x80x9clower alkylxe2x80x9d means C1-C6 alkyl.
Use of the above terms is meant to encompass substituted and unsubstituted moieties. Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl, aralkyl, alkenyl, alkynyl, aryl, carboxyalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of xe2x80x94Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94S(O)xe2x80x94. Rings may be substituted multiple times.
The terms xe2x80x9celectron-withdrawingxe2x80x9d or xe2x80x9celectron-donatingxe2x80x9d refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, incorporated herein by reference.
Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium and trifluoromethyl among others. Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto and disulfide among others. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.
The most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkylamino), amine lower mercapto, mercaptoalkyl, alkylthio and alkyldithio.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present. These compounds are designated by the symbols xe2x80x9cRxe2x80x9d or xe2x80x9cS,xe2x80x9d depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers are designated (xc2x1). Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Geometric isomers can also exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbonxe2x80x94carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbonxe2x80x94carbon double bond are designated as being in the Z or E configuration wherein the term xe2x80x9cZxe2x80x9d represents substituents on the same side of the carbonxe2x80x94carbon double bond and the term xe2x80x9cExe2x80x9d represents substituents on opposite sides of the carbonxe2x80x94carbon double bond. The arrangement of substituents around a carbocyclic ring are designated as cis or trans wherein the term xe2x80x9ccisxe2x80x9d represents substituents on the same side of the plane of the ring and the term xe2x80x9ctransxe2x80x9d represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated cis/trans.
As is apparent from the foregoing descriptions, the compounds of Formula I are useful in a variety of forms, i.e., with various substitutions as identified. Examples of particularly desirable compounds are quite diverse, and many are mentioned herein.
Compounds of the present invention include, but are not limited to: 1-(6-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyrimidin-4-yl)-piperidine-3-carboxylic acid, 4-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-6-(3-(2H-tetrazol-5-yl)-piperidin-1-yl)-pyrimidine, 4-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-6-(4-(2H-tetrazol-5-yl)-piperidin-1-yl)-pyrimidine, (1-(6-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyrimidin-4-yl)-piperidin-3-yl)-menthanol, 2-(1-(6-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyrimidin-4-yl)-piperidin-4-yl)-ethanol, N-(1-(4-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyridin-2-yl)-pyrrolidin-3-yl)-acetamide, 1-(4-(4-(2-methoxy-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyridin-2-yl)-pyrrolidine-3-ol, N-1-(4-(4-(2-methoxy-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyridin-2-yl)-pyrrolidine-3-yl)-acetamide, N-1-(4-(4-(2-methoxy-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyridin-2-yl)-pyrrolidine-3-yl)-acetamide, N-(1-(4-(4-(2,3-dihydro-benzo(1,4)dioxin-6-ylsulfanyl)-3-trifluoromethyl-phenyl)-pyridin-2-yl)-pyrrolidin-3-yl)-acetamide, 4xe2x80x2-(4-(2,3-dihydro-benzo(1,4)dioxin-6-ylsulfanyl)-3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-(1,2xe2x80x2)bipyridinyl-4-carboxylic acid and 4xe2x80x2-(4-(2,3-dihydro-benzo(1,4)dioxin-6-ylsulfanyl)-3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-(1,2xe2x80x2)bipyridinyl-3-carboxylic acid.
Abbreviations which have been used in the schemes and the examples which follow are: DCM for methylene dichloride; EWG for electron withdrawing group; NMP for N-methylpyrrolidinone; sat. for saturated; THF for tetrahydrofuran; TFA for trifluoroacetic acid; ; BINAP for 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl; DMSO for dimethylsulfoxide; MCPBA for meta-chloroperbenzoic acid; DMF for dimethylformamide; TLC for thin layer chromatography; HPLC for high pressure liquid chromatography; APCI for atmospheric pressure chemical ionization; ESI for electrospray ionization; DCI for direct chemical ionization; LFA for lymphocyte function-associated antigen; and ICAM for intercellular adhesion molecule.
The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more pharmaceutically-acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term xe2x80x9cparenteralxe2x80x9d administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically-acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agarxe2x80x94agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
The compounds of the present invention may be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids. By xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically-acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically-acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically-acceptable basic addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically-acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 0.1 to about 50 mg, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally or intravenously to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
The compounds and processes of the present invention may be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention can be prepared.
Scheme 1 describes compounds of Formula I, which contain an oxazole ring n=0, Y=N, B=O, D=C). In Scheme 1, and likewise in Schemes 2 and 4, the substituent X is a leaving group. In Scheme 1, Aryl methyl ketone 1, with an appropriate substitution (R1-2 and R4-5), and a leaving group X, reacts with an aryl thiol to give a biaryl sulfide 2. Biarylsulfide 2 can be converted into an alpha-bromomethyl ketone 3 using a variety of reagents including Bu4NBr3. Condensation of 3 with a urea gives a desired oxazole compound 4. 
Another method of preparing compounds of Formula I containing an oxazole ring (n=0, Y=N, B=O, D=C) is illustrated in Scheme 2. In Scheme 2, an aryl methyl keton 1 is converted into an alpha-hydroxymethyl ketone 5, which then can be reacted with an arythiol to give a biaryl sulfide 6. Acid-catalyzed condensation of 6 with KOGN affords a 2-hydroxy oxazole 7, which can be converted into a 2-chloro-oxazole 8 using POCl3. Displacement of the chloride of 8 with an amine gives a desired 2-amino-oxazole 9. 
Scheme 3 describes the synthesis of a class of compounds of Formula I containing thioazole ring (n=0, Y=N, B=S, D=C). In Scheme 3, biaryl sulfide alpha-bromomethy ketone 3 can be prepared following the procedure outline in Scheme 1. Condensation of with a properly substituted thiourea gives a desired 2-aminothioazole 10. 
Another class of compounds of Formula I are compounds containing a pyrimidine ring, for example 4,6-disubstituted pyrimidines (n=1, Y=C, B=N, Z=C, D=N). Scheme 4 describes one procedure for the preparation of this class of compounds. Reaction of a biaryl sulfide methyl ketone 2 with diethyl carbonate under base-catalysis leads to a beta-ketoester 11. Condensation of 11 with formamidine gives a 4-hydroxy pyrimidine 12. which can be converted into a 4-chloropyrimidine 13. Displacement of the chloride of 13 by an amine gives a desired 4-amino-pyrimidine 14. 
An alternative synthesis of 4,6-disubstituted pyrimidines is illustrated in Scheme 5. In Scheme 5, nucleophilic substitution of an aryl fluoride 15 with an aryl thio under base-catalysis gives a biaryl sulfide 16. Transmetallation of 16 with n-BuLi/ZnCl2 followed by Pd-catalyzed cross-coupling with a 4,6-diiodopyrimidine leads to an iodopyrimidine 17. Reaction of 17 with a selected amine gives a desired 4-aminopyrimidine 14. 
Yet another class of compounds of Formula I are compounds containing a pyridine ring, for example 2,4-disubstituted pyridines (n=1, Y=C, B=N, Z=C, D=C). Scheme 5 describes one procedure for the preparation of this class of compounds. In Scheme 6, Pd catalyzed cross-coupling of a properly substituted 1-bromo-4-fluoro-benzene 15 and 4-pyridine boronic acid gives compound 18. Oxidation of 18 with MCPBA leads to a pyridinium oxide 19. Displacement of the fluoride of 19 with an aryl thio affords biarylsulfide 20. Treatment of 20 with POCl3, leads to 2-chloropyridine 21. Finally, reaction of 21 with a selected amine gives a desired 2-aminopyridine 22. 
The compounds and processes of the present invention will be better understood in connection with the following examples which are intended as an illustration of and not a limitation upon the scope of the invention.